Benzylpenicillin, i.e. 3,3-dimethyl-7-oxo-6-[(phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]hepta ne- 2-carboxylic acid commonly referred to as penicillin G, is a widely prescribed antibacterial agent. Benzylpenicillin is available in the free acid, salt, and ester forms and is formulated for oral or parenteral use.
Benzylpenicillin is conventionally prepared by fermentation. A penicillin-producing microorganism is cultured in a medium containing a source of nitrogen, a source of carbon and energy, various inorganic salts, and a sidechain precursor. It has been known since the 19403 s that in order to obtain relatively pure benzylpenicillin in suitable yields as the fermentation product rather than a mixture of penicillins, a sidechain precursor should be present in the medium.
Phenylacetic acid and its salts such as potassium phenylacetic acid are conventionally employed as benzylpenicillin sidechain precursors. Other benzylpenicillin precursors disclosed by Singh et al, J. Bact. Vol. 56, p. 339-355 (1948), include octadecanol phenylacetate, phenylacetamide, phenylacetyl-D,L-alanine, phenylacetylglycine, .beta.-phenylethylamine, and D,L-phenylalanine. Various phenylacetic acid derivatives are taught as benzylpenicillin precursors by Behrens et al, Journal of Biological Chem., Vol. 175, p. 751-764, Tabenkin et al, Archives of Biochemistry and Biophysics, Vol. 38, p. 43-48, and the Editorial Board of the Monograph on the Chemistry of Penicillins, Science, Vol. 106, p. 503-505. Substituted phenylacetic acids are also disclosed as benzylpenicillin precursors by Umezawa et al, Chem. Abst., Vol. 43, p. 3060f and N-(2-hydroxyethyl)phenylacetamide is disclosed by Perlman et al in U.S. Pat. No. 2,641,567.
Nara et al in Japanese Patent 28432 (1974) disclose producing benzylpenicillin or Penicillin V in a fermentation medium containing n-paraffins as the carbon source and phenylacetic acid or phenoxyacetic acid as the sidechain precursor.
Similarly, Pidoplichko et al, Chem. Abst., Vol. 71, p. 46903r, disclose that Penicillium species are able to use hydrocarbons, hexadecane, higher secondary alcohols, C.sub.17-20 fatty acids, and higher paraffins as the sole source of carbon.